Central Nervous System Hypersomnia Research Articles

Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine clinical practice guideline.

This guideline establishes clinical practice recommendations for the treatment of central disorders of hypersomnolence in adults and children. The American Academy of Sleep Medicine commissioned a task force of experts in sleep medicine to develop recommendations and assign strengths to each recommendation, based on a systematic review of the literature and an assessment of the evidence using the GRADE process. The task force provided a summary of the relevant literature and the quality of evidence, the balance of benefits and harms, patient values and preferences, and resource use considerations that support the recommendations. The AASM Board of Directors approved the final recommendations. The following recommendations are intended to guide clinicians in choosing a specific treatment for central disorders of hypersomnolence in adults and children. Each recommendation statement is assigned a strength ("strong" or "conditional"). A "strong" recommendation (ie, "We recommend…") is one that clinicians should follow under most circumstances. A "conditional" recommendation (ie, "We suggest…") is one that requires that the clinician use clinical knowledge and experience and strongly consider the individual patient's values and preferences to determine the best course of action. Under each disorder, strong recommendations are listed in alphabetical order followed by the conditional recommendations in alphabetical order. The section on adult patients with hypersomnia because of medical conditions is categorized based on the clinical and pathological subtypes identified in ICSD-3. The interventions in all the recommendation statements were compared to no treatment. We recommend that clinicians use modafinil for the treatment of narcolepsy in adults. (STRONG). We recommend that clinicians use pitolisant for the treatment of narcolepsy in adults. (STRONG). We recommend that clinicians use sodium oxybate for the treatment of narcolepsy in adults. (STRONG). We recommend that clinicians use solriamfetol for the treatment of narcolepsy in adults. (STRONG). We suggest that clinicians use armodafinil for the treatment of narcolepsy in adults. (CONDITIONAL). We suggest that clinicians use dextroamphetamine for the treatment of narcolepsy in adults. (CONDITIONAL). We suggest that clinicians use methylphenidate for the treatment of narcolepsy in adults. (CONDITIONAL). We recommend that clinicians use modafinil for the treatment of idiopathic hypersomnia in adults. (STRONG). We suggest that clinicians use clarithromycin for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL). We suggest that clinicians use methylphenidate for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL). We suggest that clinicians use pitolisant for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL). We suggest that clinicians use sodium oxybate for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL). We suggest that clinicians use lithium for the treatment of Kleine-Levin syndrome in adults. (CONDITIONAL). We suggest that clinicians use armodafinil for the treatment of hypersomnia secondary to dementia with Lewy bodies in adults. (CONDITIONAL). We suggest that clinicians use modafinil for the treatment of hypersomnia secondary to Parkinson's disease in adults. (CONDITIONAL). We suggest that clinicians use sodium oxybate for the treatment of hypersomnia secondary to Parkinson's disease in adults. (CONDITIONAL). We suggest that clinicians use armodafinil for the treatment of hypersomnia secondary to traumatic brain injury in adults. (CONDITIONAL). We suggest that clinicians use modafinil for the treatment of hypersomnia secondary to traumatic brain injury in adults. (CONDITIONAL). We suggest that clinicians use modafinil for the treatment of hypersomnia secondary to myotonic dystrophy in adults. (CONDITIONAL). We suggest that clinicians use modafinil for the treatment of hypersomnia secondary to multiple sclerosis in adults. (CONDITIONAL). We suggest that clinicians use modafinil for the treatment of narcolepsy in pediatric patients. (CONDITIONAL). We suggest that clinicians use sodium oxybate for the treatment of narcolepsy in pediatric patients. (CONDITIONAL). Maski K, Trotti LM, Kotagal S, et al. Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2021;17(9):1881-1893.

A practical guide to the pharmacological and behavioral therapy of Narcolepsy.

Narcolepsy is a rare, chronic, and disabling central nervous system hypersomnia; two forms can be recognized: narcolepsy type 1 (NT1) and narcolepsy type 2 (NT2). Its etiology is still largely unknown, but studies have reported a strong association between NT1 and HLA, as well as a pathogenic association with the deficiency of cerebrospinal hypocretin-1. Thus, the most reliable pathogenic hypothesis is an autoimmune process destroying hypothalamic hypocretin-producing cells. A definitive cure for narcolepsy is not available to date, and although the research in the field is highly promising, up to now, current treatments have aimed to reduce the symptoms by means of different pharmacological approaches. Moreover, overall narcolepsy symptoms management can also benefit from non-pharmacological approaches such as cognitive behavioral therapies (CBTs) and psychosocial interventions to improve the patients’ quality of life in both adult and pediatric-affected individuals as well as the well-being of their families. In this review, we summarize the available therapeutic options for narcolepsy, including the pharmacological, behavioral, and psychosocial interventions.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-021-01051-4.

Clinician-Focused Overview and Developments in Polysomnography.

Purpose of ReviewPolysomnography (PSG) represents a fundamental diagnostic tool used in the evaluation of sleep disorders. It represents a simultaneous recording of sleep staging, eye movements, electromyographic tone, respiratory parameters, and electrocardiogram. It is particularly helpful in the assessment of sleep-disordered breathing and its management, propensity for excessive sleepiness, complex behaviors during sleep, including motor disturbances of sleep, sleep-related epilepsy, and parasomnias. This review is intended to summarize the indications for PSG, the limitations and challenges of this diagnostic tool, indications for home sleep apnea testing options, and new developments and trends in polysomnography.Recent FindingsThe polysomnogram is fundamentally important in the evaluation of sleep-disordered breathing in the setting of cardiovascular comorbidities and neurologic conditions such as neuromuscular disease, stroke, and epilepsy and in the evaluation of dream enactment behavior in the setting of REM sleep behavior disorder (RBD). Because RBD is predictive of neurodegenerative disorders, recent data highlights the importance of PSG in corroborating the diagnosis of RBD and identifying people who may be at risk. However, due to cost as well as limitations in access to care, further testing has been developed and implemented including the home sleep apnea test (HSAT). The evolution of consumer wearable devices has also been a growing trend in sleep medicine; however, few have received appropriate validation.SummaryPSG has been used in both the clinical and research settings and remains the gold standard clinical diagnostic test for suspected obstructive sleep apnea (OSA) or central sleep apnea (CSA). Clinicians must be familiar with the basic indications for a PSG but also recognize when it is absolutely required. At this time, the PSG is essential in the evaluation of nocturnal hypoventilation disorders of sleep, periodic limb movements of sleep, and central nervous system hypersomnia (in the absence of CSF hypocretin) when combined with the multiple sleep latency test (MSLT) and is probably the only way to help differentiate among complex behaviors during sleep, especially in the setting of RBD. The capacity to establish an early diagnostic risk of potential dementia would be of critical importance once neuroprotective agents become available.

Therapeutic Strategies for Mitigating Driving Risk in Patients with Narcolepsy.

Narcolepsy is a central nervous system hypersomnia disorder characterized by uncontrollable episodes of daytime sleep, sleep state instability, and cataplexy (sudden loss of muscle tone precipitated by emotion). Individuals with narcolepsy report more frequent sleep-related crashes, near crashes, and drowsy driving than drivers with other sleep disorders. As such, evaluating risk of sleep-related crashes is of great importance for this patient population. There are no established guidelines for ensuring driving safety in patients with narcolepsy; however, many providers currently use a combination of subjective report, report of prior crashes or near-misses, report of previously falling asleep while driving, sleepiness screening tools, and maintenance of wakefulness testing (MWT) to determine risk. Driving simulator tests, though often unavailable to the clinician, provide data to support the use of MWT for evaluation of alertness in drivers with narcolepsy. Treatments such as modafinil may improve driving performance; however, the impact of other treatments such as stimulants and sodium oxybate on driving has not been extensively studied. Behavioral and lifestyle modifications may also reduce risk, including scheduled naps, driving only short distances, and avoiding driving after meals, sedating medications, and alcohol intake. Even with effective treatment, alertness in patients with narcolepsy may never reach that of normal drivers; however, studies have suggested that narcolepsy patients may be able to drive safely with appropriate limitations.

Narcolepsy treatment: pharmacological and behavioral strategies in adults and children.

Narcolepsy is a disabling, rare, and chronic sleep disorder, currently classified as distinct central nervous system hypersomnia in narcolepsy type 1 (NT1) and narcolepsy type 2 (NT2). Although today a reliable pathogenic hypothesis identifies the cause of NT1 as an autoimmune process destroying hypocretin-producing cells, there is no cure for narcolepsy, and the symptomatic pharmacological available treatments are not entirely effective for all symptoms. Behavioral therapies play a synergistic role in the disease treatment. We here review the available therapeutic options for narcolepsy, including symptomatic pharmacological treatments as well as behavioral and psychosocial interventions that could help clinicians improve the quality of life of patients with narcolepsy in adulthood and childhood.

Excessive daytime sleepiness in narcolepsy and central nervous system hypersomnias.

Excessive daytime sleepiness (EDS) is the core complaint of central nervous system (CNS) hypersomnias. In this mini-review, we summarized EDS features in CNS hypersomnias to provide a guide for differential diagnosis purposes. A review of recent literature was performed to provide an update in CNS hypersomnias. At clinical evaluation, narcolepsy patients report a good restorative potential of sleep together with the frequent occurrence of dreaming even during short-lasting naps. These features are mirrored by the neurophysiological evidence of REM sleep at sleep onset (SOREMP) during the Multiple Sleep Latency Test (MSLT), a specific marker. Conversely, patients with idiopathic hypersomnia (IH) complain sleep inertia and prolonged nocturnal sleep. Polysomnographic studies show high sleep propensity on the MSLT or high 24-h total sleep time during continuous monitoring. Patients with insufficient sleep syndrome (ISS) can present with variable clinical EDS features in between narcolepsy and IH. ISS diagnosis is based on the clinical evidence of nocturnal sleep curtailment (weekdays versus vacations) associated with the disappearance of EDS complaint after sleep extension. Polysomnographic data are not required, but when the MSLT is performed, ISS patients can present with SOREMP arising from non-REM stage 2 sleep (vs narcolepsy patients entering into SOREM most frequently from wakefulness). Kleine-Levin Syndrome is characterized by recurrent episodes of enormously prolonged sleep time lasting days associated with abnormal cognition and behavior intermixed by asymptomatic periods, a sleep pattern that can be well documented by actigraphy. Different CNS hypersomnias present with specific features of EDS are useful to guide the clinician to apply and interpret appropriate neurophysiological investigations.

Chapter 23 - Clinical neurophysiology of CNS hypersomnias

Central nervous system hypersomnias (narcolepsy type 1 and type 2, idiopathic hypersomnia, and Kleine-Levin syndrome) are orphan sleep disorders in which the predominant symptom is excessive daytime sleepiness. The evaluation of sleepiness requires rigorous clinical and neurophysiologic approaches that may include the Epworth Sleepiness Scale, multiple sleep latency tests, and the maintenance of wakefulness test. However, to date, no gold standard measurement of excessive sleepiness exists, and there are no quantifiable biologic markers. The main pathophysiologic feature of central hypersomnias is thought to reflect a deficiency of arousal systems, rather than an overactivity of sleep systems or an imbalance between those systems. Impaired neurotransmission of hypocretin/orexin (neuropeptides of the lateral hypothalamus) is involved in the neurobiology of narcolepsy with cataplexy (NT1). NT1 is a well-characterized disorder, due to the destruction of hypocretin/orexin neurons by a probable autoimmune process. The biologic hallmarks of the other central hypersomnias remain unknown, and neurophysiologic biomarkers are still of major importance for the diagnosis and characterization of those disorders.

Diagnosis and Management of Narcolepsy.

AbstractType 1 narcolepsy is caused by deficient hypocretin signaling in the central nervous system (CNS), and is distinct from other primary CNS hypersomnias, which seem to lay along a spectrum from type 2 narcolepsy to idiopathic hypersomnia. There appears to be a strong autoimmune diathesis to the development of type 1 narcolepsy, as evidenced by the near universal presence of HLA-DQB1*06:02 in patients. Growing knowledge of the immunogenetic basis of the disease is supported by genetic studies and seasonal variation of type 1 narcolepsy incidence following winter upper respiratory infections (e.g., strep throat and influenza). Despite improved diagnostic accuracy of adding cerebrospinal fluid hypocretin measurement to the traditional workup, recognition of the disorder remains limited by its moderate prevalence and atypical manifestations in different ethnic groups. Treatments are currently symptom-based, and have been extended to other hypersomnias with mixed results.

0654 PSG AND MSLT CHARACTERIZATION OF REM SLEEP WITHOUT ATONIA AND REM BEHAVIOR DISORDER AMONG PEDIATRIC PATIENTS WITH NARCOLEPSY

In this study, we aim to determine the prevalence of nocturnal RWA and RBD in a drug-naïve pediatric narcolepsy population and compare findings to pediatric patients with other central nervous system hypersomnias and controls. We additionally aim to determine the prevalence of RWA and RBD during daytime REM bouts captured during MSLT testing. Given that RSWA, RBD and cataplexy are thought to underlie dysfunction within REM on/off neurons, we hypothesize that RSWA and RBD will be found only during the daytime and nighttime REM periods among patients with narcolepsy type 1. Based on sleep study results and clinical history, we grouped subjects as narcolepsy type 1 (N1, n=11), narcolepsy type 2 (N2, n=4), idiopathic hypersomnia (IH, n=5) and controls (C, n=11). Mean age of patients was 13 years and 49% were female. RSWA and RBD were scored based on American Academy of Sleep Medicine specifications. We calculated a RSWA index for each subject (number of REM epochs with RSWA/total REM epochs). On the PSG, we only detected RBD among N1 patients (2/11, 18%) but found no difference in the frequency of RSWA among groups (P=0.18). Notably, all N1 patients had RSWA and the RSWA index was 5.5x higher on their nocturnal PSGs compared to all other groups (P=0.002). On MSLT, 82% of N1 patients had RSWA and RSWA was not detected in any other groups. The two N1 patients with RBD during the PSG also had RBD on the MSLT. RSWA is uniquely detected among N1 patients on the MSLT but not the PSG. However, the frequency of nocturnal RSWA is markedly higher in N1 pediatric patients compared to other groups, findings consistent with adult narcolepsy data. Our findings have practical implications about scoring pediatric MSLTs as epochs of REM may lack the classic atonia in N1. Furthermore, the frequent presence of RSWA across day and night REM periods and higher mean RSWA index in the N1 group suggest that greater hypocretin loss results in phenotypic changes in REM sleep in addition to dysregulated REM sleep bouts. None.

Improvement in daytime sleepiness with clarithromycin in patients with GABA-related hypersomnia: Clinical experience

The macrolide antibiotic clarithromycin can enhance central nervous system excitability, possibly by antagonism of GABA-A receptors. Enhancement of GABA signaling has recently been demonstrated in a significant proportion of patients with central nervous system hypersomnias, so we sought to determine whether clarithromycin might provide symptomatic benefit in these patients. We performed a retrospective review of all patients treated with clarithromycin for hypersomnia, in whom cerebrospinal fluid enhanced GABA-A receptor activity in vitro in excess of controls, excluding those with hypocretin deficiency or definite cataplexy. Subjective reports of benefit and objective measures of psychomotor vigilance were collected to assess clarithromycin's effects. Clinical and demographic characteristics were compared in responders and non-responders. In total, 53 patients (38 women, mean age 35.2 (SD 12.8 years)) were prescribed clarithromycin. Of these, 34 (64%) reported improvement in daytime sleepiness, while 10 (19%) did not tolerate its side effects, and nine (17%) found it tolerable but without symptomatic benefit. In those who reported subjective benefit, objective corroboration of improved vigilance was evident on the psychomotor vigilance task. Twenty patients (38%) elected to continue clarithromycin therapy. Clarithromycin responders were significantly younger than non-responders. Clarithromycin may be useful in the treatment of hypersomnia associated with enhancement of GABA-A receptor function. Further evaluation of this novel therapy is needed.

Test-Retest Reliability of the Multiple Sleep Latency Test in Narcolepsy without Cataplexy and Idiopathic Hypersomnia

Differentiation of narcolepsy without cataplexy from idiopathic hypersomnia relies entirely upon the multiple sleep latency test (MSLT). However, the test-retest reliability for these central nervous system hypersomnias has never been determined. Patients with narcolepsy without cataplexy, idiopathic hypersomnia, and physiologic hypersomnia who underwent two diagnostic multiple sleep latency tests were identified retrospectively. Correlations between the mean sleep latencies on the two studies were evaluated, and we probed for demographic and clinical features associated with reproducibility versus change in diagnosis. Thirty-six patients (58% women, mean age 34 years) were included. Inter -test interval was 4.2 ± 3.8 years (range 2.5 months to 16.9 years). Mean sleep latencies on the first and second tests were 5.5 (± 3.7 SD) and 7.3 (± 3.9) minutes, respectively, with no significant correlation (r = 0.17, p = 0.31). A change in diagnosis occurred in 53% of patients, and was accounted for by a difference in the mean sleep latency (N = 15, 42%) or the number of sleep onset REM periods (N = 11, 31%). The only feature predictive of a diagnosis change was a history of hypnagogic or hypnopompic hallucinations. The multiple sleep latency test demonstrates poor test-retest reliability in a clinical population of patients with central nervous system hypersomnia evaluated in a tertiary referral center. Alternative diagnostic tools are needed.

The Current State of Sleep Medicine Education in US Neurology Residency Training Programs: Where Do We Go from Here?

To evaluate the current state of sleep medicine educational resources and training offered by US neurology residency programs. In 2010, a 20-item peer reviewed Sleep Education Survey (SES) was sent to neurology residency program directors surveying them about sleep medicine educational resources used in teaching residents. Pearson product momentum correlation was used to determine correlation of program attributes with resident interest in pursuing a career in sleep medicine. Of the programs completing the survey, 81% listed a formal sleep rotation and 24% included a forum for sleep research. A variety of innovative approaches for teaching sleep medicine were noted. Program directors noted that 5.7% residents entered sleep medicine fellowship training programs in the preceding 5 years. Programs that had a more substantial investment in sleep medicine teaching resources were more likely to report residents entering a sleep medicine training program. This is the first report providing an analysis of the current state of sleep medicine training in US Neurology Residency Programs. Our data provide evidence that investment by the residency program in sleep education may enhance the ultimate decision by the neurology trainee to pursue a career in sleep medicine.

Different sleep onset criteria at the multiple sleep latency test (MSLT): an additional marker to differentiate central nervous system (CNS) hypersomnias

Excessive daytime sleepiness (EDS) has different correlates in non-rapid eye movement (NREM) [idiopathic hypersomnia (IH) without long sleep time] and REM sleep [narcolepsy without cataplexy (NwoC) and narcolepsy with cataplexy (NC)]-related hypersomnias of central origin. We analysed sleep onset characteristics at the multiple sleep latency test (MSLT) applying simultaneously two sleep onset criteria in 44 NC, seven NwoC and 16 IH consecutive patients referred for subjective EDS complaint. Sleep latency (SL) at MSLT was assessed both as the time elapsed to the occurrence of a single epoch of sleep Stage 1 NREM (SL) and of unequivocal sleep [three sleep Stage 1 NREM epochs or any other sleep stage epoch, sustained SL (SusSL)]. Idiopathic hypersomnia patients showed significantly (P<0.0001) longer SusSL than SL (7.7±2.5 versus 5.6±1.3 min, respectively) compared to NwoC (5.8±2.5 versus 5.3±2.2 min) and NC patients (4.1±3 versus 3.9±3 min). A mean difference threshold between SusSL and SL ≥27 s reached a diagnostic value to discriminate IH versus NC and NwoC sufferers (sensitivity 88%; specificity 82%). Moreover, NC patients showed better subjective sleepiness perception than NwoC and IH cases in the comparison between naps with or without sleep occurrence. Simultaneous application of the two widely used sleep onset criteria differentiates IH further from NC and NwoC patients: IH fluctuate through a wake-Stage 1 NREM sleep state before the onset of sustained sleep, while NC and NwoC shift abruptly into a sustained sleep. The combination of SusSL and SL determination at MSLT should be tested as an additional objective differential criterion for EDS disorders.

Csf Histamine Contents in Narcolepsy, Idiopathic Hypersomnia and Obstructive Sleep Apnea Syndrome

To (1) replicate our prior result of low cerebrospinal fluid (CSF) histamine levels in human narcolepsy in a different sample population and to (2) evaluate if histamine contents are altered in other types of hypersomnia with and without hypocretin deficiency. Cross sectional studies. Sixty-seven narcolepsy subjects, 26 idiopathic hypersomnia (IHS) subjects, 16 obstructive sleep apnea syndrome (OSAS) subjects, and 73 neurological controls were included. All patients were Japanese. Diagnoses were made according to ICSD-2. We found significant reductions in CSF histamine levels in hypocretin deficient narcolepsy with cataplexy (mean ± SEM; 176.0 ± 25.8 pg/mL), hypocretin non-deficient narcolepsy with cataplexy (97.8 ± 38.4 pg/mL), hypocretin non-deficient narcolepsy without cataplexy (113.6 ± 16.4 pg/mL), and idiopathic hypersomnia (161.0 ± 29.3 pg/mL); the levels in OSAS (259.3 ± 46.6 pg/mL) did not statistically differ from those in the controls (333.8 ± 22.0 pg/mL). Low CSF histamine levels were mostly observed in non-medicated patients; significant reductions in histamine levels were evident in non-medicated patients with hypocretin deficient narcolepsy with cataplexy (112.1 ± 16.3 pg/mL) and idiopathic hypersomnia (143.3 ± 28.8 pg/mL), while the levels in the medicated patients were in the normal range. The study confirmed reduced CSF histamine levels in hypocretin-deficient narcolepsy with cataplexy. Similar degrees of reduction were also observed in hypocretin non-deficient narcolepsy and in idiopathic hypersomnia, while those in OSAS (non central nervous system hypersomnia) were not altered. The decrease in histamine in these subjects were more specifically observed in non-medicated subjects, suggesting CSF histamine is a biomarker reflecting the degree of hypersomnia of central origin.

CSF Histamine Contents in Narcolepsy, Idiopathic Hypersomnia and Obstructive Sleep Apnea Syndrome

To (1) replicate our prior result of low cerebrospinal fluid (CSF) histamine levels in human narcolepsy in a different sample population and to (2) evaluate if histamine contents are altered in other types of hypersomnia with and without hypocretin deficiency. Cross sectional studies. Sixty-seven narcolepsy subjects, 26 idiopathic hypersomnia (IHS) subjects, 16 obstructive sleep apnea syndrome (OSAS) subjects, and 73 neurological controls were included. All patients were Japanese. Diagnoses were made according to ICSD-2. We found significant reductions in CSF histamine levels in hypocretin deficient narcolepsy with cataplexy (mean +/- SEM; 176.0 +/- 25.8 pg/mL), hypocretin non-deficient narcolepsy with cataplexy (97.8 +/- 38.4 pg/mL), hypocretin non-deficient narcolepsy without cataplexy (113.6 +/- 16.4 pg/mL), and idiopathic hypersomnia (161.0 +/- 29.3 pg/ mL); the levels in OSAS (259.3 +/- 46.6 pg/mL) did not statistically differ from those in the controls (333.8 +/- 22.0 pg/mL). Low CSF histamine levels were mostly observed in non-medicated patients; significant reductions in histamine levels were evident in non-medicated patients with hypocretin deficient narcolepsy with cataplexy (112.1 +/- 16.3 pg/ mL) and idiopathic hypersomnia (143.3 +/- 28.8 pg/mL), while the levels in the medicated patients were in the normal range. The study confirmed reduced CSF histamine levels in hypocretin-deficient narcolepsy with cataplexy. Similar degrees of reduction were also observed in hypocretin non-deficient narcolepsy and in idiopathic hypersomnia, while those in OSAS (non central nervous system hypersomnia) were not altered. The decrease in histamine in these subjects were more specifically observed in non-medicated subjects, suggesting CSF histamine is a biomarker reflecting the degree of hypersomnia of central origin.

Clinical caveat: prior sleep deprivation can affect the MSLT for days

It is common practice to forcibly awaken patients from an all-night polysomnographic study prior to performance of a multiple sleep latency test (MSLT); either for reasons of protocol or for the convenience of the laboratory personnel. We report a case of a young woman who, by formal sleep study criteria, received the erroneous diagnosis of narcolepsy due to the effects of severe sleep deprivation, and document that the effects of prior sleep deprivation require more than one night of ad libitum sleep. Forced awakening prior to MSLT may permit sleep deprivation or delayed sleep phase syndrome to masquerade as narcolepsy or idiopathic central nervous system (CNS) hypersomnia.

Etiologies and sequelae of excessive daytime sleepiness

Excessive dynamic sleepiness (EDS), the primary complaint of patients seen in sleep clinics, affects up to 12% of the general population. The effects of EDS can be debilitating and even life threatening. Patients with EDS may exhibit psychosocial distress, decreased work or school performance, and increased risk for accidents. The differential diagnosis of EDS requires objective assessments, such as polysomnography and the Multiple Sleep Latency Test. There are four major causes of EDS: (1) central nervous system (CNS) pathologic abnormalities, such as narcolepsy and idiopathic CNS hypersomnia; (2) qualitative or quantitative sleep deficiencies, such as sleep apnea and insufficient nocturnal sleep; (3) misalignments of the body's circadian pacemaker with the environment (eg, jet lag or shift work); and (4) drugs, which can increase sleepiness either therapeutically or as a side effect. Depending on etiology, management strategies for EDS include extension of time in bed, naps, surgery, various medical devices (eg, oral appliances, continuous positive airway pressure), and pharmacotherapy. Pharmacotherapy is generally achieved with stimulants, such as amphetamine sulfate, methylphenidate, and pemoline or newer, safer compounds like modafinil.

HLA‐DR restriction‐fragment‐length polymorphisms in narcolepsy

Seventeen white patients from the Stanford Sleep Disorders Clinic complaining of excessive daytime somnolence (EDS) were selected for restriction-fragment-length polymorphism (RFLP) studies. Fourteen of the patients with clinically diagnosed narcolepsy were seropositive for DR2. RFLP analysis of these patients compared with a homozygous DR2-Dw2 cell line failed to reveal any polymorphism when digested with six restriction endonucleases and hybridized with three different cDNA probes. None of the three patients with central nervous system hypersomnia, a syndrome similar to narcolepsy, were DR2-positive. We conclude that any polymorphism of the DR beta, DQ alpha, or DQ beta genes of DR2 narcoleptics that might distinguish them from DR2 normals cannot be resolved through RFLP analysis.

Association Between HLA Antigens and Different Types of Hypersomnia

<h3>To the Editor.—</h3> A close association has been reported between HLA antigens and narcolepsy.^1-3Over the past two years we compared various types of hypersomnia in 56 patients. Thirty-four narcoleptics and 13 patients with idiopathic central nervous system hypersomnia, all unrelated and white, were included in the statistics (Table). These patients were diagnosed on the basis of a clinical interview and polygraphic recordings of at least five daytime naps. Polygraphic recordings were scored blind with regard to the results of HLA determinations. All narcoleptics exhibited excessive daytime sleepiness, cataplexy, and sleep-onset rapid eye movement periods during nap recordings. All idiopathic hypersomniacs had severe excessive daytime sleepiness without cataplexy and short sleep latencies but no sleep-onset rapid eye movement periods during naprecordings. Sleep apnea and nocturnal myoclonus were ruled out in all idiopathic hypersomniac patients by two all-night polygraphic recordings. Fifty-four HLA antigens of loci A, B, C, and

HLA antigens in narcolepsy and idiopathic central nervous system hypersomnolence.

Several studies have shown familial incidence of narcolepsy and idiopathic central nervous system (CNS) hypersomnia. HLA antigen studies performed in mongoloid and caucasoid narcoleptic patients on the A, B, and C loci have yielded conflicting results. The aim of this study is to document a possible association between the HLA system, including the DR locus and excessive daytime somnolence. Thirty-one narcoleptic patients and 10 idiopathic hypersomniac patients were selected and typed for 54 HLA antigens. A family with narcoleptic members in 3 generations was also studied. HLA-DR2 was found in 100% of narcoleptic patients. The frequency of HLA-A3 and B7, which are in linkage disequilibrium with DR2 was also increased in this group. Idiopathic hypersomniac patients showed an increase of HLA-Cw2, DR5, and B27, three antigens known to be in linkage disequilibrium. In the family study, narcoleptic patients were also HLA-DR2; moreover, 3 subjects, one of whom was narcoleptic, were HLA-DR2 as a result of recombination (i.e., genetic crossing-over). These results locate the hypothetic gene associated with narcolepsy more precisely, and indicate that narcolepsy and idiopathic CNS hypersomnolence are two different entities.